TERC and TERT gene mutations in patients with bone marrow failure and the significance of telomere length measurements - PubMed (original) (raw)

. 2009 Jan 8;113(2):309-16.

doi: 10.1182/blood-2008-07-166421. Epub 2008 Oct 17.

Elena Pumbo, Jennifer Ivanovich, Ping An, Richard T Maziarz, Ulrike M Reiss, Deborah Chirnomas, Akiko Shimamura, Adrianna Vlachos, Jeffrey M Lipton, Rakesh K Goyal, Frederick Goldman, David B Wilson, Philip J Mason, Monica Bessler

Affiliations

TERC and TERT gene mutations in patients with bone marrow failure and the significance of telomere length measurements

Hong-Yan Du et al. Blood. 2009.

Abstract

Dyskeratosis congenita (DC) is a rare inherited form of bone marrow failure (BMF) caused by mutations in telomere maintaining genes including TERC and TERT. Here we studied the prevalence of TERC and TERT gene mutations and of telomere shortening in an unselected population of patients with BMF at our medical center and in a selected group of patients referred from outside institutions. Less than 5% of patients with BMF had pathogenic mutations in TERC or TERT. In patients with BMF, pathogenic TERC or TERT gene mutations were invariably associated with marked telomere shortening (<< 1st percentile) in peripheral blood mononuclear cells (PBMCs). In asymptomatic family members, however, telomere length was not a reliable predictor for the presence or absence of a TERC or TERT gene mutation. Telomere shortening was not pathognomonic of DC, as approximately 30% of patients with BMF due to other causes had PBMC telomere lengths at the 1st percentile or lower. We conclude that in the setting of BMF, measurement of telomere length is a sensitive but nonspecific screening method for DC. In the absence of BMF, telomere length measurements should be interpreted with caution.

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Figures

Figure 1

Figure 1

In vitro telomerase activity of the TERC RNA and TERT variants in WI-38 VA-13 cells. WI-38 VA-13 cells were transfected with a plasmid expressing the mutant or WT TERT cDNA sequences and a plasmid expressing the respective WT or mutant or TERC RNA. Telomerase activity was determined using a quantitative PCR-based TRAP assay. Activity is shown in comparison to the activity obtained after transfection with WT (= 1.0). Values above each column are the average of triplicate experiments. Error bars represent SD, * indicates the difference between the variant, and WT is statistically significant at the level of .05. In vitro telomerase activities of the TERT mutants H412Y, P704S, Y846C, and H876Q have been reported previously.

Figure 2

Figure 2

Telomere lengths in PBMC from patients with BMF. Telomere lengths in PBMC were measured by flow cytometric fluorescence in situ hybridization. (A) Telomere length in 234 healthy control subjects between the ages of 1 day and 94 years. The 1st, 5th, 25th, 50th, 75th, 95th, 99th percentiles of healthy controls are shown. (B) Telomere length in 160 patients with BMF from whom telomere measurements were obtained. (C) Telomere length in patients enrolled in the study with the diagnosis of DC. The red squares highlight patients with DC, while gray circles represent the remaining patients with BMF. (D) Telomere lengths in patients with DBA (highlighted in blue). (E) Telomere length in patients with SDS (highlighted in pink). (F) Telomere length in patients with MDS (highlighted in green). Arrows indicate patients in whom a pathogenic C35T TERC gene mutation was identified. (G) Telomere length in patients with PNH (highlighted in brown). (H) Telomere length in patients with aplastic anemia not otherwise classified (AA, highlighted in purple). Arrows indicate patients in whom a pathogenic TERT gene mutation was identified (from left to right; Y846C/H876Q, A716V, A716V). Stippled arrows indicate patients with the variant H412Y. (I) Telomere length in patients with other forms of IBMFS (Pearson syndrome, Fanconi anemia, and FPD, from left to right, highlighted in gold).

Figure 3

Figure 3

Telomere lengths in patients with DC and first-degree family members. (A) Patients with DC due to a TERC gene mutation. (B) Patients with DC due to a TERT gene mutation. (C) Patients with DC due to a DKC1 gene mutation. People with signs of BMF are shown in black; family members without BMF are shown in gray. Heterozygous mutation carriers are indicated with a half-filled symbol; filled symbol indicates homozygosity (hemizygosity/compound heterozygosity) for the mutation. (D) Telomere length in 41 subjects with a de novo TERT gene deletion due to a chromosome deletion syndrome that includes the TERT gene (5p- syndrome).

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